1. Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia.
- Author
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Río P, Navarro S, Wang W, Sánchez-Domínguez R, Pujol RM, Segovia JC, Bogliolo M, Merino E, Wu N, Salgado R, Lamana ML, Yañez RM, Casado JA, Giménez Y, Román-Rodríguez FJ, Álvarez L, Alberquilla O, Raimbault A, Guenechea G, Lozano ML, Cerrato L, Hernando M, Gálvez E, Hladun R, Giralt I, Barquinero J, Galy A, García de Andoín N, López R, Catalá A, Schwartz JD, Surrallés J, Soulier J, Schmidt M, Díaz de Heredia C, Sevilla J, and Bueren JA
- Subjects
- Adolescent, Adult, Bone Marrow Cells cytology, Child, Child, Preschool, Fanconi Anemia genetics, Fanconi Anemia physiopathology, Female, Genetic Vectors genetics, Hematopoietic Stem Cells metabolism, Humans, Infant, Lentivirus genetics, Male, Mutation genetics, Spain epidemiology, Targeted Gene Repair, Transduction, Genetic, Young Adult, Fanconi Anemia therapy, Fanconi Anemia Complementation Group A Protein genetics, Genetic Therapy, Hematopoietic Stem Cell Transplantation
- Abstract
Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date
1,2 . Mutations in FANCA account for more than 60% of FA cases worldwide3,4 . Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life5,6 . In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.- Published
- 2019
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